Viral Etiology and Clinical Characteristics of Acute Respiratory Tract Infections in Hospitalized Children in Southern Germany (2014-2018).

Background: Viral acute respiratory tract infections (ARTIs) are a leading cause of hospitalization in infants and young children. Methods: During the winter seasons of 2014-2018, hospitalized children (<18 years) with symptoms of ARTI were prospectively included at the University Hospital Heidelberg, Germany. Nasopharyngeal swabs were obtained for multiplex molecular analysis of 10 groups of respiratory viruses, and clinical data were obtained using a standardized questionnaire. Results: Of 1353 children included in this study, 1142 (84.4%) were positive for ≥1 viral pathogen. Virus monoinfection was detected in 797 (69.8%) children, whereas 345 (30.2%) children had coinfections with 2-4 viral pathogens. Respiratory syncytial virus (RSV), rhinovirus, and influenza virus were the main pathogens detected. RSV-positive children had significantly more often lower ARTIs, including symptoms of severe cough, wheezing, chest indrawing, tachypnea, and pulmonary rales. Hospitalized children aged <6 months represented the largest age group with detection of ≥1 viral pathogen (455/528 [86.2%] children). Coinfection was more frequent in younger children and, particularly for RSV with rhinovirus, significantly associated with more severe respiratory symptoms (P = .01). Conclusions: A better understanding of the etiology of viral ARTIs among hospitalized children plays a key role for future strategies in prevention, control, and treatment of respiratory viral infections.

RSV-CLASS -Clinical Assessment Severity Score: An easy-to-use clinical disease severity score for respiratory syncytial virus infection in hospitalized children.

Respiratory syncytial virus (RSV) is the most common cause of acute respiratory tract infection in infants and young children often leading to severe disease requiring hospitalization. However, validated tools for systematic assessment of disease severity are lacking. This study aimed at creating and validating a standardized, simple-to-use disease severity score for RSV infection in children-the RSV-CLASS (Clinical Assessment Severity Score). Therefore, data from over 700 RSV-infected children over six winter seasons (2014-2020) was analyzed using univariate and multiple regression analyses for the prediction of lower respiratory tract infection (LRTI) as a proxy for a severe course of the disease. Testing a broad range of respiratory symptoms, they eventually yielded seven items. Performing stepwise selection, these were reduced to the final four items: cough, tachypnea, rales, and wheezing, each receiving one point in the proposed score named RSV-CLASS. The score was calculated for children in two cohorts A and B, one for development and one for validation, with an area under the curve of 0.90 and 0.87, respectively. With a score value of 3 or 4, 97.8% and 100% of the children, respectively, were admitted with LRTI and classified correctly. The RSV-CLASS is a disease severity score based on a neutral, analytical approach using prospective data from a large study cohort. It will contribute to systematically assessing the disease severity of RSV infection and can be used for evidence-based clinical decision-making as well as for research settings.

[Updated recommendations on the treatment of infectious diseases in refugees in childhood and adolescence in Germany (situation as of 30 March 2022), registered as S1 guidelines (AWMF-Register Nr. 048-017)]. / Aktualisierte Empfehlungen zur infektiologischen Versorgung von Flüchtlingen im Kindes- und Jugendalter in Deutschland (Stand 30. März 2022), angemeldet als S1-Leitlinie (AWMF-Register Nr. 048-017): Stellungnahme der Deutschen Gesellschaft für Pädiatrische Infektiologie e. V. (DGPI), der Gesellschaft für Tropenpädiatrie und Internationale Kindergesundheit e. V. (GTP), des Berufsverbandes der Kinder- und Jugendärzte e. V. (BVKJ) und der Deutschen Gesellschaft für Kinder- und Jugendmedizin e. V. (DGKJ), unter Mitarbeit des Berufsverbands der Ärztinnen und Ärzte des Öffentlichen Gesundheitsdienstes e. V. (BVÖGD), der Deutschen Gesellschaft für Kinderchirurgie e. V. (DGKCH), der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe e. V. (DGGG), Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin (DEGAM), des Bündnis Kinder- und Jugendgesundheit e. V. (früher Deutsche Akademie für Kinder- und Jugendmedizin, DAKJ), der Deutschen Gesellschaft für Tropenmedizin, Reisemedizin und Globale Gesundheit e. V. (DTG), der Deutschen Gesellschaft für Globale und Tropenchirurgie e. V. (DTC) und der Pädiatrisch Infektiologischen Gruppe Schweiz (PIGS).

Background: Based on 190,000 applications for asylum, Germany remains a top destination for refugees and asylum seekers in Europe. The updated recommendations are considered evidence-based and targeted guidelines for the diagnosis and prevention of infectious diseases in underage refugees and asylum seekers. Objective: The objective of these recommendations is to guide medical staff in the care of minor refugees, in particular to:1. assure early recognition and completion of incomplete vaccination status,2. diagnose and treat common infectious diseases,3. recognize and treat imported infectious diseases that are considered uncommon to the German healthcare system. Material and methods: The recommendations have been formally written to be published as AWMF S1 guidelines.This includes a representative expert panel appointed by several professional societies, and formal adoption of the recommendations by the board of directors of all societies concerned. Results: Recommendations are given for the medical evaluation of minor refugees, including medical history and physical examination. A blood count as well as screening for tuberculosis and hepatitis B should be offered to all minor refugees. In addition, screening for other infectious diseases like hepatitis C, HIV or schistosomiasis should be considered depending on age and country of origin. Vaccinations are recommended based on both age and country of origin. Conclusion: As thousands of minor refugees continue to seek shelter in Germany every year, professional health care with adequate financial support needs to be established to ensure an appropriate medical treatment of this particularly vulnerable population.

Transcellular blood-brain barrier disruption in malaria-induced reversible brain edema.

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as brain swelling at the acute stage is difficult to study in humans and animal models with reliable induction of reversible edema are not known. In this study, we show that reversible brain swelling in experimental murine CM can be induced reliably after single vaccination with radiation-attenuated sporozoites as proven by in vivo high-field magnetic resonance imaging. Our results provide evidence that brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In adult CM patients magnetic resonance imaging demonstrate microhemorrhages in more than one third of patients with reversible edema, emphasizing similarities of the experimental model and human disease. Our data suggest that targeting transcellular BBBD may represent a promising adjunct therapeutic approach to reduce edema and may improve neurological outcome.

RSVpredict: An Online Tool to Calculate the Likelihood of Respiratory Syncytial Virus Infection in Children Hospitalized With Acute Respiratory Disease.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection in young children. Early detection of RSV infection can avoid unnecessary diagnostic and therapeutic intervention and is required to prevent the nosocomial spread of RSV infection in pediatric hospitals. We developed a web tool to calculate the probability of RSV infection in children hospitalized with acute respiratory tract infection (ARTI) (RSVpredict). METHODS: During winter seasons 2014/2015 to 2017/2018, 1545 children hospitalized with clinical symptoms of ARTI at the University Hospital Heidelberg/Germany were prospectively included. Medical information was reported on a standardized data sheet, and nasopharyngeal swabs were obtained for multiplex real-time polymerase chain reaction analyses. We applied logistic regression to develop a prediction model and developed a web-based application to predict the individual probability of RSV infection. RESULTS: Duration of clinical symptoms ≥2 days on admission, calendar month of admission, admission for lower respiratory tract infection, the presence of cough and rale and younger age were associated with RSV infection (P < 0.05). Those data were included in the prediction model (RSVpredict, https://web.imbi.uni-heidelberg.de/rsv/). RSVpredict is a web-based application to calculate the risk of RSV infection in children hospitalized with ARTI. The prediction model is based on easily accessible clinical symptoms and predicts the individual probability of RSV infection risk immediately. CONCLUSIONS: Pediatricians might use the RSVpredict to take informed decisions on further diagnostic and therapeutic intervention, including targeted RSV testing in children with relevant RSV infection risk.

MRI of Iron Oxide Nanoparticles and Myeloperoxidase Activity Links Inflammation to Brain Edema in Experimental Cerebral Malaria.

Purpose To investigate the association of inflammation and brain edema in a cerebral malaria (CM) mouse model with a combination of bis-5-hydroxy-tryptamide-diethylenetriaminepentaacetate gadolinium, referred to as MPO-Gd, and cross-linked iron oxide nanoparticle (CLIO-NP) imaging. Materials and Methods Female wild-type (n = 23) and myeloperoxidase (MPO) knock-out (n = 5) mice were infected with the Plasmodium berghei ANKA strain from May 2016 to July 2018. Seven healthy mice served as control animals. At a Rapid Murine Coma and Behavioral Scale (RMCBS) score of less than 15, mice underwent MRI at 9.4 T and received gadodiamide, MPO-Gd, or CLIO-NPs. T1-weighted MRI was used to assess MPO activity, and T2*-weighted MRI was used to track CLIO-NPs. Immunofluorescent staining and flow cytometric analyses characterized CLIO-NPs, MPO, endothelial cells, and leukocytes. An unpaired, two-tailed Student t test was used to compare groups; Spearman correlation analysis was used to determine the relationship of imaging parameters to clinical severity. Results MPO-Gd enhancement occurred in inflammatory CM hotspots (olfactory bulb > rostral migratory stream > brainstem > cortex, P < .05 for all regions compared with control mice; mean olfactory bulb signal intensity ratio: 1.40 ± 0.07 vs 0.96 ± 0.01, P < .01). The enhancement was reduced in MPO knockout mice (mean signal intensity ratio at 60 minutes: 1.13 ± 0.04 vs 1.40 ± 0.07 in CM, P < .05). Blood-brain barrier compromise was suggested by parenchymal gadolinium enhancement, leukocyte recruitment, and endothelial activation. CLIO-NPs accumulated mainly intravascularly and at the vascular endothelium. CLIO-NPs were also found in the choroid plexus, indicating inflammation of the ventricular system. Blood-cerebrospinal fluid barrier breakdown showed correlation with brain swelling (r2: 0.55, P < .01) and RMCBS score (r2: 0.75, P < .001). Conclusion Iron oxide nanoparticle imaging showed strong inflammatory involvement of the microvasculature in a murine model of cerebral malaria. Furthermore, bis-5-hydroxy-tryptamide-diethylenetriaminepentaacetate gadolinium imaging depicted parenchymal and intraventricular inflammation. This combined molecular imaging approach links vascular inflammation to breakdown of the blood-brain barrier and blood-cerebrospinal fluid barrier that correlate with global brain edema and disease severity. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Kiessling in this issue.

Protection from experimental cerebral malaria with a single intravenous or subcutaneous whole-parasite immunization.

Cerebral malaria is a life-threatening complication of Plasmodia infection and a major cause of child mortality in Sub-Saharan Africa. We report that protection from experimental cerebral malaria in the rodent model is obtained by a single intravenous or subcutaneous whole-parasite immunization. Whole-parasite immunization with radiation-attenuated sporozoites was equally protective as immunization with non-attenuated sporozoites under chemoprophylaxis. Both immunization regimens delayed the development of blood-stage parasites, but differences in cellular and humoral immune mechanisms were observed. Single-dose whole-parasite vaccination might serve as a relatively simple and feasible immunization approach to prevent life-threatening cerebral malaria.

Performance of the Alere i RSV assay for point-of-care detection of respiratory syncytial virus in children.

BACKGROUND: Respiratory syncytial virus (RSV) is the most important cause of severe acute respiratory tract infection in young children. Alere i RSV is a novel molecular rapid test which identifies respiratory syncytial virus in less than 13 min. METHODS: We evaluated the clinical performance of the Alere i RSV assay in a pediatric point-of-care setting during winter season 2016 / 2017. Test results from 518 nasopharyngeal swab samples were compared to a real-time reverse transcription PCR reference standard. RESULTS: The overall sensitivity and specificity of the Alere i RSV test assay was 93% (CI95 89% - 96%) and 96% (CI95 93% - 98%), respectively. Alere i RSV performed well in children of all age groups. An optimal sensitivity of 98% (CI95 94% - 100%) and specificity of 96% (CI95 90% - 99%) was obtained in children < 6 months. In children ≥ 2 years, sensitivity and specificity remained at 87% (CI95 73% - 96%) and 98% (CI95 92% - 100%), respectively. False negative Alere i RSV test results mostly occurred in samples with low viral load (mean CT value 31.1; CI95 29.6 - 32.6). The Alere i RSV assay is easy to use and can be operated after minimal initial training. Test results are available within 13 min, with most RSV positive samples being identified after approximately 5 min. CONCLUSION: The Alere i RSV assay has the potential to facilitate the detection of RSV in pediatric point-of-care settings.

In Vivo Tracking of Edema Development and Microvascular Pathology in a Model of Experimental Cerebral Malaria Using Magnetic Resonance Imaging.

Cerebral malaria is a sign of severe malarial disease and is often a harbinger of death. While aggressive management can be life-saving, the detection of cerebral malaria can be difficult. We present an experimental mouse model of cerebral malaria that shares multiple features of the human disease, including edema and microvascular pathology. Using magnetic resonance imaging (MRI), we can detect and track the blood-brain barrier disruption, edema development, and subsequent brain swelling. We describe multiple MRI techniques that can visualize these pertinent pathological changes. Thus, we show that MRI represents a valuable tool to visualize and track pathological changes, such as edema, brain swelling, and microvascular pathology, in vivo.

Evaluation of Alere i RSV for Rapid Detection of Respiratory Syncytial Virus in Children Hospitalized with Acute Respiratory Tract Infection.

Alere i RSV is a novel rapid test which applies a nicking enzyme amplification reaction to detect respiratory syncytial virus in point-of-care settings. In this study, we evaluated the Alere i RSV assay by using frozen nasopharyngeal swab samples that were collected in viral transport medium from children hospitalized with acute respiratory tract infection during the 2015-2016 winter season. Alere i RSV assay results were compared to those for Altona RealStar RSV real-time reverse transcription-PCR (RT-PCR). We found that the overall sensitivity and specificity of the Alere i RSV test was 100% (95% confidence intervals [CI], 93% to 100%) and 97% (95% CI, 89% to 100%), respectively. Positive samples were identified within 5 to 7 min from sample collection. Overall, the Alere i RSV test performed well compared to the RT-PCR assay and has the potential to facilitate the detection of RSV in point-of-care settings.

Reverse-transcription loop-mediated isothermal amplification for rapid detection of respiratory syncytial virus directly from nasopharyngeal swabs.

Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infection in young infants and a major cause of nosocomial infection in pediatric care. Currently available RSV point-of-care tests are of limited sensitivity and relatively expensive. We developed and evaluated a novel RSV rapid test for use at point-of-care, based on reverse-transcription loop-mediated isothermal amplification (RT-LAMP) for direct testing of nasopharyngeal swab specimens. RT-LAMP can detect RSV within 30min, without the need for RNA extraction. The sensitivity of our RT-LAMP assay was 70-80% in comparison to RT-PCR. The RT-LAMP test sensitivity is at least equivalent to currently available rapid antigen detection tests (RADT), and the cost of RT-LAMP test reagents is only approximately 10% of that of commercially available RADT tests. RT-LAMP appears to be an attractive alternative to RADT, particularly in settings with limited financial resources. Future improvements could include lyophilization of test reagents and automated read-out of RT-LAMP results.

High-Density Peptide Arrays for Malaria Vaccine Development.

The development of an efficacious and practicable vaccine conferring sterile immunity towards a Plasmodium infection represents a not yet achieved goal. A crucial factor for the impact of a given anti-plasmodial subunit vaccine is the identification of the most potent parasitic components required to induce protection from both infection and disease. Here, we present a method based on a novel high-density peptide array technology that allows for a flexible readout of malaria antibodies. Peptide arrays applied as a screening method can be used to identify novel immunogenic antibody epitopes under a large number of potential antigens/peptides. Ultimately, discovered antigen candidates and/or epitope sequences can be translated into vaccine prototype design. The technology can be further utilized to unravel antibody-mediated immune responses (e.g., involved in the establishment of semi-immunity) and moreover to confirm vaccine potency during the process of clinical development by verifying the induced antibody responses following vaccination.

Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream.

It is poorly understood how progressive brain swelling in experimental cerebral malaria (ECM) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. We therefore monitored in the Plasmodium berghei ANKA-C57BL/6 murine ECM model, disease manifestation and progression clinically, assessed by the Rapid-Murine-Coma-and-Behavioral-Scale (RMCBS), and by high-resolution in vivo MRI, including sensitive assessment of early blood-brain-barrier-disruption (BBBD), brain edema and microvascular pathology. For histological correlation HE and immunohistochemical staining for microglia and neuroblasts were obtained. Our results demonstrate that BBBD and edema initiated in the olfactory bulb (OB) and spread along the rostral-migratory-stream (RMS) to the subventricular zone of the lateral ventricles, the dorsal-migratory-stream (DMS), and finally to the external capsule (EC) and brainstem (BS). Before clinical symptoms (mean RMCBS = 18.5±1) became evident, a slight, non-significant increase of quantitative T2 and ADC values was observed in OB+RMS. With clinical manifestation (mean RMCBS = 14.2±0.4), T2 and ADC values significantly increased along the OB+RMS (p = 0.049/p = 0.01). Severe ECM (mean RMCBS = 5±2.9) was defined by further spread into more posterior and deeper brain structures until reaching the BS (significant T2 elevation in DMS+EC+BS (p = 0.034)). Quantitative automated histological analyses confirmed microglial activation in areas of BBBD and edema. Activated microglia were closely associated with the RMS and neuroblasts within the RMS were severely misaligned with respect to their physiological linear migration pattern. Microvascular pathology and ischemic brain injury occurred only secondarily, after vasogenic edema formation and were both associated less with clinical severity and the temporal course of ECM. Altogether, we identified a distinct spatiotemporal pattern of microglial activation in ECM involving primarily the OB+RMS axis, a distinct pathway utilized by neuroblasts and immune cells. Our data suggest significant crosstalk between these two cell populations to be operative in deeper brain infiltration and further imply that the manifestation and progression of cerebral malaria may depend on brain areas otherwise serving neurogenesis.

An Economic Evaluation of the Posttreatment Prophylactic Effect of Dihydroartemisinin-Piperaquine Versus Artemether-Lumefantrine for First-Line Treatment of Plasmodium falciparum Malaria Across Different Transmission Settings in Africa.

Malaria disproportionately affects young children. Clinical trials in African children showed that dihydroartemisinin-piperaquine (DP) is an effective antimalarial and has a longer posttreatment prophylactic (PTP) effect against reinfections than other artemisinin-based combination therapies, including artemether-lumefantrine (AL). Using a previously developed Markov model and individual patient data from a multicenter African drug efficacy trial, we assessed the economic value of the PTP effect of DP versus AL in pediatric malaria patients from health-care provider's perspective in low-to-moderate and moderate-to-high transmission settings under different drug co-payment scenarios. In low-to-moderate transmission settings, first-line treatment with DP was highly cost-effective with an incremental cost-effectiveness ratio of US$5 (95% confidence interval [CI] = -76 to 196) per disability-adjusted life year (DALY) averted. In moderate-to-high transmission settings, DP first-line treatment led to a mean cost saving of US$1.09 (95% CI = -0.88 to 3.85) and averted 0.05 (95% CI = -0.08 to 0.22) DALYs per child per year. Our results suggested that DP might be superior to AL for first-line treatment of uncomplicated childhood malaria across a range of transmission settings in Africa.

Addition of histamine to subcutaneously injected Plasmodium berghei sporozoites increases the parasite liver load and could facilitate whole-parasite vaccination.

BACKGROUND: Whole-parasite immunization remains the benchmark in malaria vaccine development. A major bottleneck in the translation of whole-parasite immunization towards routine vaccination is the mode of administration, since high degrees of protection are currently only achieved by intravenous, and not by intradermal or subcutaneous injection of viable parasites. It is known that only a small proportion of subcutaneously administered parasites reach the subsequent liver stage and low parasite liver load was shown to be associated with low protective efficacy. The objective of this analysis was to evaluate whether the liver load following subcutaneous parasite injection could be augmented by co-administration of pro-inflammatory or anti-coagulatory drugs. METHODS: In the C57BL/6 Plasmodium berghei ANKA model, the clinical outcome (time to patent blood stage infection and survival) and relative parasite liver load was assessed in mice infected by subcutaneous or intramuscular sporozoite (SPZ) administration in the presence or absence of histamine and heparin supplementation in comparison to intravenously administered SPZ. In addition, a vaccination experiment was carried out to assess the protective efficacy of an improved, histamine-supplemented subcutaneous immunization regimen. RESULTS: The parasite liver load following subcutaneous SPZ administration can be significantly increased by co-administration of histamine and heparin. A dose-dependent relation between parasite liver load and histamine dosage was observed. However, despite a relatively high parasite liver load, the protective efficacy of histamine-supplemented subcutaneous immunization remains inferior as compared to intravenous SPZ administration. CONCLUSIONS: Histamine supplementation might facilitate the future development of a non-intravenous whole-parasite vaccine. Further investigations are needed to reveal the effect of histamine supplementation and subcutaneous SPZ administration on the acquisition of protective immunity.

Screening for respiratory syncytial virus and isolation strategies in children hospitalized with acute respiratory tract infection.

Nosocomial infection with respiratory syncytial virus (RSV) is an important health risk in pediatric care but is largely preventable by efficient infection control measures. Commonly applied rapid antigen detection tests (RADTs) miss a considerable number of RSV-infected patients. The objective of our analysis was to evaluate whether readily available host parameters are associated with false-negative RADT, and to assess how these parameters could be applied in an optimized RSV isolation strategy.We retrospectively analyzed a cohort of 242 children under the age of 2 years hospitalized with acute respiratory tract infection to identify host parameters associated with false-negative RADT test result. We subsequently simulated the outcome of different isolation strategies based on RADT result and host parameters in view of the overall isolation efficacy.Out of 242 hospitalized patients, 134 (55%) patients were found RSV-positive by RT-PCR, whereas 108 (45%) patients were tested negative. The performance of the RADT was compared with the result obtained by reverse transcription polymerase chain reaction on the identical nasopharyngeal wash. Overall, we found that 85 patients (35%) were tested true positive, 108 (45%) were tested true negative, whereas a false-negative test result was obtained in 49 patients (20%). Duration of respiratory symptoms for >3 days and a respiratory admission diagnosis are associated with false-negative RADT result. In comparison with RADT alone, consideration of these clinical parameters and RADT result can decrease the rate of nonisolated RSV-infected patients from approximately 24% to 8% (65% RSV pretest probability).Consideration of both RADT and clinical parameters associated with false-negative RADT can result in an optimized RSV infection control policy.

Novel respiratory syncytial virus (RSV) genotype ON1 predominates in Germany during winter season 2012-13.

Respiratory syncytial virus (RSV) is the leading cause of hospitalization especially in young children with respiratory tract infections (RTI). Patterns of circulating RSV genotypes can provide a better understanding of the molecular epidemiology of RSV infection. We retrospectively analyzed the genetic diversity of RSV infection in hospitalized children with acute RTI admitted to University Hospital Heidelberg/Germany between October 2012 and April 2013. Nasopharyngeal aspirates (NPA) were routinely obtained in 240 children younger than 2 years of age who presented with clinical symptoms of upper or lower RTI. We analyzed NPAs via PCR and sequence analysis of the second variable region of the RSV G gene coding for the attachment glycoprotein. We obtained medical records reviewing routine clinical data. RSV was detected in 134/240 children. In RSV-positive patients the most common diagnosis was bronchitis/bronchiolitis (75.4%). The mean duration of hospitalization was longer in RSV-positive compared to RSV-negative patients (3.5 vs. 5.1 days; p<0.01). RSV-A was detected in 82.1%, RSV-B in 17.9% of all samples. Phylogenetic analysis of 112 isolates revealed that the majority of RSV-A strains (65%) belonged to the novel ON1 genotype containing a 72-nucleotide duplication. However, genotype ON1 was not associated with a more severe course of illness when taking basic clinical/laboratory parameters into account. Molecular characterization of RSV confirms the co-circulation of multiple genotypes of subtype RSV-A and RSV-B. The duplication in the G gene of genotype ON1 might have an effect on the rapid spread of this emerging RSV strain.

Protection against malaria by immunization with non-attenuated sporozoites under single-dose piperaquine-tetraphosphate chemoprophylaxis.

Experimental whole-parasite immunization through concurrent administration of infectious Plasmodium sporozoites with drugs that prevent pathogenic blood-stage infection represents the current benchmark in malaria vaccine development. Key questions concerning translation remain, including the requirement for single-dose drug regimens that can reliably prevent breakthrough infections. We assessed the feasibility and efficacy of immunization with single-dose piperaquine chemoprophylaxis and concurrent sporozoite administration (PPQ-CPS) in the murine P. berghei ANKA/C57BL/6 infection model. We demonstrate that PPQ-CPS is protective with an efficacy comparable to previous findings using whole-parasite immunization under chloroquine chemoprophylaxis. PPQ-CPS immunization resulted in an expansion of intrahepatic and intrasplenic effector memory CD8(+) T cells. In summary, PPQ-CPS appears to be a safe and efficacious immunization regimen in the rodent malaria model and may thus become an important improvement regarding the translation of whole-parasite immunization toward a human malaria vaccine.

Dihydroartemisinin-piperaquine vs. artemether-lumefantrine for first-line treatment of uncomplicated malaria in African children: a cost-effectiveness analysis.

BACKGROUND: Recent multi-centre trials showed that dihydroartemisinin-piperaquine (DP) was as efficacious and safe as artemether-lumefantrine (AL) for treatment of young children with uncomplicated P. falciparum malaria across diverse transmission settings in Africa. Longitudinal follow-up of patients in these trials supported previous findings that DP had a longer post-treatment prophylactic effect than AL, reducing the risk of reinfection and conferring additional health benefits to patients, particularly in areas with moderate to high malaria transmission. METHODS: We developed a Markov model to assess the cost-effectiveness of DP versus AL for first-line treatment of uncomplicated malaria in young children from the provider perspective, taking into consideration the post-treatment prophylactic effects of the drugs as reported by a recent multi-centre trial in Africa and using the maximum manufacturer drug prices for artemisinin-based combination therapies set by the Global Fund in 2013. We estimated the price per course of treatment threshold above which DP would cease to be a cost-saving alternative to AL as a first-line antimalarial drug. RESULTS: First-line treatment with DP compared to AL averted 0.03 DALYs (95% CI: 0.006-0.07) and 0.001 deaths (95% CI: 0.00-0.002) and saved $0.96 (95% CI: 0.33-2.46) per child over one year. The results of the threshold analysis showed that DP remained cost-saving over AL for any DP cost below $1.23 per course of treatment. CONCLUSIONS: DP is superior to AL from both the clinical and economic perspectives for treatment of uncomplicated P. falciparum malaria in young children. A paediatric dispersible formulation of DP is under development and should facilitate a targeted deployment of this antimalarial drug. The use of DP as first-line antimalarial drug in paediatric malaria patients in moderate to high transmission areas of Africa merits serious consideration by health policymakers.